The human immunodeficiency (HIV) is etiologically associated with a broad spectrum of diseases, including severe immune deficiency, neurological disorders, and development of secondary malignancies, most notably Kaposi's Sarcoma (KS). Since KS tissues do not harbor HIV, its role in KS pathogenesis must be indirect. We have previously developed an in vitro system to maintain long-term growth of the characteristic KS spindle cells from AIDS patients using conditioned medium from HIV or HTLV-infected cells. These cultured cells produce potent angiogenic factors that support their own growth and growth of other cells of endothelial and fibroblast origins. Furthermore, inoculation of these KS-derived cells in nude mice induced neoangiogenic lesions comprising of mouse cells histologically similar to human KS cells. Thus, the pathogenesis of KS is mediated by induction of cytokines leading to the autocrine and paracrine growth of the abnormal spindle cells and surrounding stromal endothelial and fibroblastic cells. It has been shown that HIV-1 tat gene, when introduced into the germline of mice, induced skin lesions resembling KS. Recently, we showed that the tat protein (Tat) is released from HIV-infected cells or tat-transfected cells, and directly stimulates growth proliferation of KS-derived cells. The optimal threshold of Tat for growth stimulation is much lower than that required for transactivation. In the proposal, we investigate the molecular basis and pathogenic relevance of this growth promoting activity of Tat: (1) Is this activity directly linked to the capacity of Tat to transactivate the HIV-LTR? (2) What is the nature of the uptake and release of Tat from producing cells? Is the uptake receptor mediated? Is the release due to secretion? Are there regions of Tat required for these two processes? (3) Are there cellular gene activated in the Tat-stimulated KS-cells? (4) If KS pathogenesis requires cellular gene activation, would inhibitors of these gene products (antibodies, antisense) halt the development or progression of KS in the in vivo nude mice model? These studies should shed light on the role of HIV in KS induction and provide leads for therapeutic intervention of this disease.
| Vogel, B E; Lee, S J; Hildebrand, A et al. (1993) A novel integrin specificity exemplified by binding of the alpha v beta 5 integrin to the basic domain of the HIV Tat protein and vitronectin. J Cell Biol 121:461-8 |
